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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel, 3-Arm Study of the Safety and Anti-Pruritic Efficacy of Nalbuphine HCl ER Tablets in Hemodialysis Patients with Uremic Pruritis

    Summary
    EudraCT number
    		 2013-005625-22
    Trial protocol
    		 PL   RO  
    Global end of trial date
    08 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2016
    First version publication date
    03 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TR02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02143648
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Trevi Therapeutics, Inc.
    Sponsor organisation address
    195 Church Street, 14th Floor, New Haven, United States, Connecticut 06510
    Public contact
    Clinical Trial Information, Trevi Therapeutics, Inc., 001 203304-2499, Thomas.Sciascia@trevitherapeutics.com
    Scientific contact
    Clinical Trial Information, Trevi Therapeutics, Inc., 001 203304-2499, Thomas.Sciascia@trevitherapeutics.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: • To evaluate the effects of two doses of nalbuphine HCl ER tablets on the change from baseline in the worst itch Numerical Rating Scale (NRS) in hemodialysis patients with moderate to severe uremic pruritus. • To evaluate the safety and tolerability of nalbuphine HCl ER in the study population.
    Protection of trial subjects
    An unblinded, independent Data and Safety Monitoring Board (DSMB) reviewed safety data. The DSMB periodically reviewed group-unblinded study information (on a treatment group level, using random letters instead of actual treatments) during the conduct of the study. If necessary, unblinding of individual subject data and treatment groups was possible.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 302
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Romania: 49
    Worldwide total number of subjects
    373
    EEA total number of subjects
    71
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    284
    From 65 to 84 years
    87
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 597 patients were screened of which 373 patients were randomized: 128 to nalbuphine HCl ER 60 mg BID, 120 to nalbuphine HCl ER 120 mg BID, and 125 to placebo. The safety population consisted of 369 treated patients who received at least one dose of randomized treatment.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study staff, patients, and Sponsor were blinded to treatment assignment to avoid potential bias. An unblinded, independent Data Safety Monitoring Board (DSMB) periodically reviewed safety data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nalbuphine 60 mg
    Arm description
    		 Blinded titration over 2 weeks to a target dose of 60 mg twice daily (BID) followed by 6 weeks at 60 mg BID. 128 patients were randomized to nalbuphine HCl ER 60 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID patients completed the full term of study participation through the end of the post- treatment washout.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nalbuphine hydrochloride (HCl) extended-release (ER) tablets
    Investigational medicinal product code
    Nalbuphine HCl ER
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60mg BID, Oral use

    Arm title
    		 Nalbuphine 120 mg
    Arm description
    		 Blinded titration over 2 weeks to a target dose of 120 mg BID followed by 6 weeks at 120 mg BID. 120 patients were randomized to nalbuphine HCl ER 120 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 78 (65.0%) nalbuphine HCl ER 120 mg BID patients completed the full term of study participation through the end of the post- treatment washout.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nalbuphine hydrochloride (HCl) extended-release (ER) tablets
    Investigational medicinal product code
    Nalbuphine HCl ER
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120mg BID, Oral use

    Arm title
    		 Placebo
    Arm description
    		 Placebo x 8 weeks twice daily (BID). 125 paients were rendomized to placebo. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 101 (80.8%) placebo patients completed the full term of study participation through the end of the post- treatment washout.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment was administered as oral tablets BID without regard to food. An equal number of tablets was administered to the active treatment and placebo arm for all given treatment visits over the duration of the study.

    Number of subjects in period 1
    		Nalbuphine 60 mg Nalbuphine 120 mg Placebo
    Started
    128
    120
    125
    Completed
    74
    78
    101
    Not completed
    54
    42
    24
         Consent withdrawn by subject
    11
    9
    5
         Adverse event, non-fatal
    33
    27
    7
         patient's non-compliance with protocol
    3
    3
    4
         Other
    3
    2
    4
         Death
    -
    -
    1
         Renal transplantation
    1
    1
    1
         Patient transferred from dialysis unit
    1
    -
    1
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nalbuphine 60 mg
    Reporting group description
    		 Blinded titration over 2 weeks to a target dose of 60 mg twice daily (BID) followed by 6 weeks at 60 mg BID. 128 patients were randomized to nalbuphine HCl ER 60 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID patients completed the full term of study participation through the end of the post- treatment washout.

    Reporting group title
    Nalbuphine 120 mg
    Reporting group description
    		 Blinded titration over 2 weeks to a target dose of 120 mg BID followed by 6 weeks at 120 mg BID. 120 patients were randomized to nalbuphine HCl ER 120 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 78 (65.0%) nalbuphine HCl ER 120 mg BID patients completed the full term of study participation through the end of the post- treatment washout.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo x 8 weeks twice daily (BID). 125 paients were rendomized to placebo. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 101 (80.8%) placebo patients completed the full term of study participation through the end of the post- treatment washout.

    Reporting group values
    		 Nalbuphine 60 mg Nalbuphine 120 mg Placebo Total
    Number of subjects
    		 128 120 125 373
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 100 90 94 284
        From 65-84 years
    		 27 30 30 87
        85 years and over
    		 1 0 1 2
    Age continuous
    Units: years
        median (standard deviation)
    		 56.5 ( 12 ) 55 ( 12.2 ) 56 ( 13 ) -
    Gender categorical
    Units: Subjects
        Male
    		 70 69 74 213
        Female
    		 58 51 51 160
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID, 78 (65.0%) nalbuphine HCl ER 120 mg BID, and 101 (80.8%) placebo patients completed the full term of study participation through the end of the post-treatment washout.

    Subject analysis set title
    Modified-Intent-to-Treat (MITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified-Intent-to-Treat (MITT) analysis included all but two randomized patients, both excluded because they did not have any post-baseline evaluation. The demographic and baseline characteristics for the MITT population were similar to those of the safety population. Modified intent-to-treat population consisted of: Nalbuphine 60 mg: 128; Nalbuphine 120 mg: 120; Placebo: 123.

    Subject analysis sets values
    		 Safety Modified-Intent-to-Treat (MITT)
    Number of subjects
    369
    371
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    282
    282
        From 65-84 years
    85
    87
        85 years and over
    2
    2
    Age continuous
    Units: years
        median (standard deviation)
    56 ( 12.4 )
    56 ( 12.4 )
    Gender categorical
    Units: Subjects
        Male
    211
    212
        Female
    158
    159

    End points

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    End points reporting groups
    Reporting group title
    Nalbuphine 60 mg
    Reporting group description
    		 Blinded titration over 2 weeks to a target dose of 60 mg twice daily (BID) followed by 6 weeks at 60 mg BID. 128 patients were randomized to nalbuphine HCl ER 60 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID patients completed the full term of study participation through the end of the post- treatment washout.

    Reporting group title
    Nalbuphine 120 mg
    Reporting group description
    		 Blinded titration over 2 weeks to a target dose of 120 mg BID followed by 6 weeks at 120 mg BID. 120 patients were randomized to nalbuphine HCl ER 120 mg BID. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 78 (65.0%) nalbuphine HCl ER 120 mg BID patients completed the full term of study participation through the end of the post- treatment washout.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo x 8 weeks twice daily (BID). 125 paients were rendomized to placebo. The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 101 (80.8%) placebo patients completed the full term of study participation through the end of the post- treatment washout.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID, 78 (65.0%) nalbuphine HCl ER 120 mg BID, and 101 (80.8%) placebo patients completed the full term of study participation through the end of the post-treatment washout.

    Subject analysis set title
    Modified-Intent-to-Treat (MITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified-Intent-to-Treat (MITT) analysis included all but two randomized patients, both excluded because they did not have any post-baseline evaluation. The demographic and baseline characteristics for the MITT population were similar to those of the safety population. Modified intent-to-treat population consisted of: Nalbuphine 60 mg: 128; Nalbuphine 120 mg: 120; Placebo: 123.

    Primary: Mean Reduction in Worst itch NRS During the Evaluation Period (MITT Population)

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    End point title
    		 Mean Reduction in Worst itch NRS During the Evaluation Period (MITT Population) [1]
    End point description
    Primary TR02 outcome variable: change from baseline value to the Evaluation Period value (Weeks 7 and 8) in a patient’s mean Worst Itch NRS for each dose of nalbuphine, separately, and placebo. Statistical significance for the comparison of each nalbuphine arm to placebo was defined as a two-sided p-value ≤ 0.05. A statistically significant reduction compared to placebo in Worst Itch NRS was demonstrated for the nalbuphine 120 mg BID (p=0.017) (Table 1).
    End point type
    Primary
    End point timeframe
    Change from baseline value to the Evaluation Period value (Weeks 7 and 8).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please refer to the attached table - Table 1: TR02 Mean Reduction in Worst itch NRS During the Evaluation Period (MITT Population)
    End point values
    		 Modified-Intent-to-Treat (MITT)
    Number of subjects analysed
    274
    Units: itch NRS
        arithmetic mean (standard deviation)
    -3.1 ( 2.3 )
    Attachments
    		 Table 1
    No statistical analyses for this end point

    Post-hoc: Mean Reduction in Worst Itch NRS during the Evaluation Period Patients with Severe UP (NRS≥7) (MITT Population)

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    End point title
    		 Mean Reduction in Worst Itch NRS during the Evaluation Period Patients with Severe UP (NRS≥7) (MITT Population)
    End point description
    An additional analysis for the subgroup of patients with severe uremic pruritus (Worst Itch NRS ≥7) at baseline was undertaken. As can be seen in Table 2, a statistically significant mean reduction in Worst Itch NRS was demonstrated for nalbuphine HCl ER 120 mg BID compared with placebo (p=0.007); the mean (SD) reduction was -4.48 (2.50) points and the least square mean difference from placebo was -1.39 points. Mean reduction for nalbuphine HCl ER tablets 60 mg BID with severe UP was not significantly greater than for placebo, and did not meet the criteria for being clinically meaningful.
    End point type
    Post-hoc
    End point timeframe
    Change from baseline value to the Evaluation Period value (Weeks 7 and 8).
    End point values
    		 Modified-Intent-to-Treat (MITT)
    Number of subjects analysed
    137
    Units: inch NRS
        arithmetic mean (standard deviation)
    -3.7 ( 2.6 )
    Attachments
    		 Table 2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At least one Treatment Emergent Adverse Event (TEAE) was reported by 94/317 (74.6%) patients in the nalbuphine 60 mg BID arm, 88/264 (73.3%) patients in the nalbuphine 120 mg BID arm, and 75/195 (61.0%) patients in the placebo arm of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    safety population
    Reporting group description
    		 The safety population consisted of 369 treated patients who received at least one (AM or PM) dose of randomized treatment. A total of 74 (57.5%) nalbuphine HCl ER 60 mg BID, 78 (65.0%) nalbuphine HCl ER 120 mg BID, and 101 (80.8%) placebo patients completed the full term of study participation through the end of the post-treatment washout. There were no notable differences in demographics and baseline characteristics in patients across treatment groups. The demographic and baseline characteristics for the MITT population were similar to those of the safety population. One death occurred in Study TR02. A subject in the placebo group died following nephrectomy (performed for pyelonephritis) with the post-operative development of an abscess and sepsis.

    Serious adverse events
    		 safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 369 (11.65%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Local swelling
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Conversion disorder
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal arteriovenous malformation
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    5 / 369 (1.36%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 369 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 369 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 369 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    3 / 369 (0.81%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    4 / 369 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 369 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    252 / 369 (68.29%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 369 (5.96%)
         occurrences all number
    25
    Somnolence
         subjects affected / exposed
    37 / 369 (10.03%)
         occurrences all number
    43
    Gastrointestinal disorders
    Constipation
    Additional description: The total number of AEs counts all treatment-emergent AEs for patients. At each level of patient summarization, a patient is counted once if the patient reported one or more events.
         subjects affected / exposed
    16 / 369 (4.34%)
         occurrences all number
    16
    Diarrhoea
         subjects affected / exposed
    24 / 369 (6.50%)
         occurrences all number
    27
    Nausea
         subjects affected / exposed
    82 / 369 (22.22%)
         occurrences all number
    91
    Vomiting
         subjects affected / exposed
    71 / 369 (19.24%)
         occurrences all number
    86

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2014
    Clinical research Protocol TR02 v5.0 was produced for the following purposes: • To incorporate a Data and Safety Monitoring Board (DSMB) • To acknowledge hemodialysis adequacy guidelines • To incorporate clarifications, administrative changes and correction of typographical errors throughout the protocol. Previous version of the Protocol (version no. 4.0 of 24 June 2014) was submitted in Romania within initial submission.
    10 Oct 2014
    Clinical research Protocol TR02 v6.0 was produced for the following purposes: • To clarify the timing and window of visits during the Washout and Safety Follow-up Period related to the last dose of drug • To clarify the time period to calculate the total dose of erythropoiesis stimulating agent (ESA) • To clarify the lower end of the study drug dosing window. Protocol version no. 6.0 of 10 October 2014 was submitted in Poland within initial submission.
    20 Jan 2015
    Clinical research Protocol TR02 v7.0 was produced for the following purposes: • To add central cardiac core laboratory read of study ECGs • To incorporate EU directives • To incorporate clarifications, administrative changes and correction of typographical errors throughout the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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